2015 Volume 38 Issue 5 Pages 655
Pancreatic β-cells serve as a fuel sensor via secretion of insulin, which is controlled tightly by blood glucose concentration. The process of glucose-stimulated insulin secretion (GSIS) is explained as follows: Glucose, which has entered β-cells via glucose transporters (GLUT1 or 2), is phosphorylated by the rate-limiting enzyme glucokinase, which has a high Km for glucose. The product, glucose-6-phosphate, is further metabolized via glycolysis, tricarboxylic acid (TCA) cycle, and the electron transport chain to produce ATP, the central energy molecule. The increased ATP to ADP ratio in the cytosol prompts closure of ATP-sensitive K+ (KATP) channels. The resulting membrane depolarization leads to the activation of voltage-dependent Ca2+ channels, which triggers the exocytosis of insulin granules. Although this KATP channel-dependent pathway is considered to be a primary mechanism for GSIS, the involvement of KATP channel-independent actions in GSIS is also proposed. This is supported by the finding that glucose can augment the insulin secretion evoked by high K+ even under the condition where KATP channels are fully opened or closed pharmacologically. GSIS consists of two phases: a transient first phase, followed by a sustained second phase. It has been understood that the KATP channel-dependent mechanism mediates triggering of insulin secretion, while the KATP channel-independent one contributes to augmentation of insulin secretion in the second phase. Pancreatic β-cells have at least two distinct pools of insulin granules, i.e., a reserve pool and a readily releasable pool. The readily releasable pool consists of a small number of the granules docked and primed for release. The first phase of GSIS is accounted for mostly by the readily releasable pool. The second phase requires the translocation of the granules from the reserve pool to the plasma membrane.
The exocytotic process of insulin secretion has been investigated as analogous to stimulus-secretion coupling of neuronal cells. However, an apparent difference exists between them: insulin secretion is tuned over minutes to hours, whereas neurotransmitter release ends within sub-second range. Dr. Noriko Takahashi and coworkers have intensively investigated the mechanism for insulin exocytosis by applying two-photon excitation imaging to β-cells. Two-photon imaging enables one to visualize the mobilization of insulin granules in intact pancreatic islets, and makes it possible to examine the spatial profile of the exocytosis. In the first review, she presents an overview of the exocytotic process of insulin secretion, and provides a newer perspective based on recent developments in this field.
The process of granule mobilization and exocytosis is well known to be regulated by small G proteins, such as Rho, Rab, and Arf families. It is generally understood that the GDP-bound and GTP-bound forms of small G proteins are inactive and active, respectively. In contrast to this view, Dr. Toshihide Kimura and coworkers have found an active role of the GDP-bound form of Rab27a, a member of the Rab family that is highly expressed in β-cells, in the endocytotic process, and proposed a new view that GTP- and GDP-bound Rab27a regulate pre-exocytotic and endocytotic stages in membrane traffic, respectively. In the second review, they review recent progress in the understanding of the roles of Rab27a and its effectors in β-cells.
The readily releasable pool of insulin granules is known to be enlarged by second messengers such as cyclic AMP and diacylglycerol (DAG). These second messengers mediate the effects of receptor agonists such as glucagon-like peptide-1 (GLP-1) and acetylcholine, which augment GSIS. Glucose by itself can also increase the levels of cyclic AMP and DAG, implying possible involvement of these second messengers in the KATP channel-independent pathway of GSIS. Recently, Dr. Yukiko K. Kaneko and coworkers have demonstrated the obligatory role of type I diacylglycerol kinase (DGK), a metabolic enzyme for DAG, in GSIS. In the third review, they review the current understanding of the roles of DAG and DGK in β-cells and discuss their pathophysiological roles in β-cells.
The last review is on a novel mechanism for glucose sensing in β-cells. In addition to the taste cells in the tongue, sweet taste receptors are expressed in intestinal enteroendocrine cells and mediate the secretion of GLP-1 and gastric inhibitory polypeptide (GIP). Thus, sweet taste receptors are likely to function as a sugar sensor in tissues other than the tongue. Dr. Itaru Kojima and coworkers took notice of the similarity between enteroendocrine cells and pancreatic β-cells and investigated possible functioning of the sweet taste receptors in β-cells. In the last review, they present a summary of their findings on the expression of the sweet taste receptor T1R3 as a glucose sensor receptor in β-cells and its involvement in GSIS.
Considerable progress has recently been made in elucidating the machinery and regulation of insulin secretion. I hope that the present mini reviews will be helpful in better understanding in the progress. I sincerely appreciate all the authors for their significant contributions.